The Wnt gene family encodes a large class of secreted proteins related to the Int1/Wntl1 proto-oncogene and Drosophila wingless (“Wg”), a Drosophila Wnt1 homologue (Cadigan et al. (1997) Genes & Development 11:3286-3305). Wnts are expressed in a variety of tissues and organs and are required for developmental processes, including segmentation in Drosophila; endoderm development in C. elegans; and establishment of limb polarity, neural crest differentiation, kidney morphogenesis, sex determination, and brain development in mammals (Parr, et al. (1994) Curr. Opinion Genetics & Devel. 4:523-528). The Wnt pathway is a master regulator in animal development, both during embryogenesis and in the mature organism (Eastman, et al. (1999) Curr Opin Cell Biol 11: 233-240; Peifer, et al. (2000) Science 287: 1606-1609). The variety of biological processes to which they take part during embryonic development and adult homeostasis is paralleled by the diversification within genomes into Wnt orthologues (19 identified Wnts in humans) and by the capacity to activate at least three intracellular signalling pathways (Moon et al., 2002; Nelson and Nusse, 2004; Seto and Bellen, 2004), the calcium-mediated and planar polarity pathways (Strutt, 2003; Veeman et al., 2003; Kuhl, 2004) and the canonical Wnt-β-catenin pathway. In the canonical Wnt pathway, Wnt ligands bind to their Frizzled receptor of a family of 10 reported Frizzled (“Fz”) seven transmembrane domain receptors (Bhanot et al. (1996) Nature 382:225-230). So doing, they activate the cytoplasmic protein Dishevelled (Dv1-1, 2 and 3 in humans and mice) (Boutros, et al. (1999) Mech Dev 83: 27-37) and phosphorylate LRP5/6. A signal is thereby generated which prevents the phosphorylation and degradation of Armadillol/β-catenin, in turn leading to an increase in cytoplasmic β-catenin (Perrimon (1994) Cell 76:781-784). This β-catenin translocates to the nucleus where it binds TCF (T cell factor) transcription factors (also known as lymphoid enhancer-binding factor-1 (LEF1)), serving as a coactivator of TCF/LEF-induced transcription (Bienz, et al. (2000) Cell 103: 311-320; Polakis, et al. (2000) and finally leading to the increased gene expression of Wnt target genes. In the absence of Wnt, cytoplasmic β-catenin protein is constantly degraded by the action of the Axin complex, which is composed of the scaffolding protein Axin, the tumor suppressor adenomatous polyposis coli gene product (APC), casein kinase 1 (CK1), and glycogen synthase kinase 3 (GSK3). CK1 and GSK3 sequentially phosphorylate the amino terminal region of β-catenin, resulting in β-catenin recognition by β-Trcp, an E3 ubiquitin ligase subunit, and subsequent β-catenin ubiquitination and proteasomal degradation (He et al., 2004). This continual elimination of β-catenin prevents β-catenin from reaching the nucleus, and Wnt target genes are thereby repressed by the DNA-bound T cell factor/lymphoid enhancer factor (TCF/LEF) family of proteins.
An increasing number of studies suggest how Wnt signalling related disorders can be initiated not only by mutations involving APC or Axin proteins (e.g., colorectal cancer), responsible for β-catenin degradation but also by alternative mechanisms. Hyperactivating mutations at the LRP5 co-receptor level are associated with high bone-density familial autosomal dominant syndrome (Boyden et al., N Engl J. Med. 2002; 346(20):1513-21). Autocrine Wnt signaling mediated by specific Wnt ligands was in fact linked to lung (Akiri et al. Oncogene 2009 28(21):2163-72), breast (Schlange et al., Breast Cancer Res. 2007; 9(5):R63 and Matsuda et al., Breast Cancer Res. 2009; 11(3):R32) and pancreatic (Nawroth et al., PLoS One. 2007 Apr. 25; 2(4):e392) tumors, but also malignant melanoma cells spreading (O'Connell et al., J Biol. Chem. 2009 Aug. 20, Epub ahead of print). Wnt signals form a class of paracrine growth factors act to influence multiple myeloma cell growth (Derksen et al., PNAS. 2004; 101(16):6122-7). The metastatic process, an ominous feature of most malignant tumors represents an additional area of intervention for Wnt inhibitors (Nguyen et al., Cell. 2009; 138(1):51-62) or tumor recurrence in glioblastoma patients (Sakarlassen et al., PNAS 2006, 103 (44) 16466) where different pathways seem to rule primary versus recurrent tumors. Moreover, there is strong evidence of the Wnt pathway involvement in cancers such as gastric cancer (Taniguchi et al, Oncogene. 2005 Nov. 24; 24(53):7946-52), medulloblastoma (Vibhakar et al., Neuro Oncol. 2007 April; 9(2):135-44), glioblastoma (Pu et al., Cancer Gene Ther. 2009 (4):351-61), hepatocellular carcinomas (Colnot et al., Proc Natl Acad Sci USA. 2004 Dec. 7; 101(49):17216-2), basal cell carcinoma (Yang et al., Nat. Genet. 2008 September; 40(9):1130-5), leukaemia (Staal, Blood, 109, 12, 5073-5074, 2007; Tickenbrock et al., Int. J. Oncol., 33, 1215-1221, 2008; Zhao, Cancer Cell, 12, 528-541, 2007), Wilm's tumours (Rivera et al., Science, 315,642-645, 2007 and Major et al., Science, 316, 1043-1046, 2007) and Familial Adenomatous Polyposis (Kinzler et al., Science 253,661-665, 1991 and Nishisho et al., Science 253,665-669, 1991).